Synthesis, in vitro and in vivo studies, and molecular modeling of N-alkylated dextromethorphan derivatives as non-competitive inhibitors of α3β4 nicotinic acetylcholine receptor

Krzysztof Jozwiak; Katarzyna M Targowska-Duda; Agnieszka A Kaczor; Joanna Kozak; Agnieszka Ligeza; Elzbieta Szacon; Tomasz M Wrobel; Barbara Budzynska; Grazyna Biala; Emilia Fornal; Antti Poso; Irving W Wainer; Dariusz Matosiuk

doi:10.1016/j.bmc.2014.10.036

Synthesis, in vitro and in vivo studies, and molecular modeling of N-alkylated dextromethorphan derivatives as non-competitive inhibitors of α3β4 nicotinic acetylcholine receptor

Bioorg Med Chem. 2014 Dec 15;22(24):6846-56. doi: 10.1016/j.bmc.2014.10.036. Epub 2014 Oct 31.

Authors

Affiliations

¹ Department of Chemistry, Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, 4a Chodzki St., PL-20093 Lublin, Poland.
² Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, 4a Chodzki St., PL-20093 Lublin, Poland; School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, FI-70211 Kuopio, Finland.
³ Department of Chemistry, Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, 4a Chodzki St., PL-20093 Lublin, Poland; Department of Anatomy, Medical University of Lublin, 4 Jaczewskiego St., PL-20090 Lublin, Poland.
⁴ Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, 4a Chodzki St., PL-20093 Lublin, Poland.
⁵ Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, 4a Chodzki St., PL-20093 Lublin, Poland.
⁶ Department of Chemistry, Catholic University of Lublin, al. Krasnicka 102, PL-20718 Lublin, Poland.
⁷ School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, FI-70211 Kuopio, Finland.
⁸ Laboratory of Clinical Investigation, Division of Intramural Research Programs, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
⁹ Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, 4a Chodzki St., PL-20093 Lublin, Poland. Electronic address: darek.matosiuk@umlub.pl.

PMID: 25464883
DOI: 10.1016/j.bmc.2014.10.036

Abstract

9 N-alkylated derivatives of dextromethorphan are synthesized and studied as non-competitive inhibitors of α3β4 nicotinic acetylcholine receptors (nAChRs). In vitro activity towards α3β4 nicotinic acetylcholine receptor is determined using a patch-clamp technique and is in the micromolar range. Homology modeling, molecular docking and molecular dynamics of ligand-receptor complexes in POPC membrane are used to find the mode of interactions of N-alkylated dextromethorphan derivatives with α3β4 nAChR. The compounds, similarly as dextromethorphan, interact with the middle portion of α3β4 nAChR ion channel. Finally, behavioral tests confirmed potential application of the studied compounds for the treatment of addiction.

Keywords: Dextromethorphan; Nicotinic acetylcholine receptors; Non-competitive inhibitors; α3β4 nicotinic acetylcholine receptor.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites
Cell Line
Dextromethorphan / chemical synthesis
Dextromethorphan / chemistry*
Dextromethorphan / pharmacology
Ligands
Lipid Bilayers / chemistry
Lipid Bilayers / metabolism
Male
Molecular Docking Simulation
Motor Activity / drug effects
Nicotinic Antagonists / chemical synthesis*
Nicotinic Antagonists / chemistry
Nicotinic Antagonists / pharmacology
Patch-Clamp Techniques
Phosphatidylcholines / chemistry
Protein Binding
Protein Structure, Tertiary
Rats
Rats, Wistar
Receptors, Nicotinic / chemistry
Receptors, Nicotinic / metabolism*

Substances

Ligands
Lipid Bilayers
Nicotinic Antagonists
Phosphatidylcholines
Receptors, Nicotinic
nicotinic receptor alpha3beta4
Dextromethorphan
1-palmitoyl-2-oleoylphosphatidylcholine

Grants and funding

Intramural NIH HHS/United States